Preparation of crystalline polymorphs of fosinopril sodium

ABSTRACT

A new procedure is described for the selective preparation of crystalline polymorphs A and B of fosinopril, especially polymorph A. The procedure described allows to avoid the use of significant quantities of water, thus resulting in a lower risk of hydrolytic degradations of the active ingredient.

FIELD OF THE TECHNIQUE

This invention relates to a new procedure for the selective preparationof the crystalline polymorphs of the sodium salt of fosinopril,especially polymorph A, which is currently used as an antihypertensiveagent belonging to the group of inhibitors of the angiotensin convertingenzyme.

PRIOR ART

Fosinopril is a derivative of phosphinic acid, of chemical name[1[S*(R*)], 2α,2β]-4-cyclohexyl-1-[[[2-methyl-1-(loxoproxy)propoxy](4-phenylbutyl)phosphinyl] acetyl]-L-proline, whose sodium salt is shownin the formula below:

Specifically, the sodium salt of fosinopril was first described in Fed.Proc., Fed. Am. Soc. Exp. Biol., 1984, 43, 733, and its preparation isdescribed in patent U.S. Pat. No. 4,873,356.

The sodium salt of fosinopril exists in two different crystalline forms,called polymorphs A and B, polymorph A being the one currently used forthe preparation of medicinal products.

European patent EP-B-0442378 describes specific procedures toselectively obtain each of the two polymorphs of the sodium salt offosinopril; as sated therein, polymorph A is the more stable one fromthe thermodynamic point of view.

As described in he above mentioned patent, when the fosinopril salt or amixture of fosinopril and an alkaline metal donor are placed in aketonic or hydroxylic solvent, or in a mixture of both, the quantity ofwater is decisive in the formation of one polymorph or the other. Form Apredominates when the quantity of water is higher than 0.2% (v/v) of thetotal water/solvent system, preferably between 1 and 3%. With waterconcentrations between 0.2% and 0.0%, polymorph B formationpredominates.

European patent EP-B-044237 specifically describes a procedure for thepreparation of polymorph A, where a mixture of fosinopril and sodiumethylhexanoate is treated in acetone containing 1.7% of water (v, v),stirred at room temperature and where polymorph A is then isolated byfiltration. Also described is that the suspension of polymorph B ofsodium fosinopril in acetone containing 2% of water, and furtherstirring of the mixture at room temperature, lead to isolation byfiltration of form A.

For polymorph B preparation, the above mentioned European patentdescribes a specific procedure consisting in evaporating to dryness apolymorph A solution in methanol at 35° C.

Regarding the obtention of polymorph A, which is the one presentlymarketed, the procedure described in the aforesaid European patent hasthe disadvantage of requiring the use of a certain quantity of water,which leads to a greater risk of producing untoward degradations of theactive substance.

As shown experimentally, sodium fosinopril in mixtures of ketonic oralcoholic solvents and water undergoes hydrolysis, leading to theformation of the corresponding phosphinic acid, a product known asfosinoprilate. This hydrolytic degradation increases with time and withhigher temperature and higher water content of the solvent.

Regarding the obtention of polymorph B, methanol solutions of sodiumfosinopril evaporated in an atomizer at room temperature have been foundto yield a form B which is spontaneously hydrated under air exposure,thereby increasing the risk of hydrolytic degradation.

Thus, there remains a need for new procedures for the preparation of thepolymorphs of the sodium salt of fosinopril, particularly polymorph A,in order to obtain a lower risk of hydrolytic degradation of the activeingredient.

Object of the Invention

The object of the invention is a procedure or the selective preparationof the crystalline polymorphs of fosinopril, particularly polymorph A,leading to a lower risk of hydrolytic degradation of the activeingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the IR spectrum of polymorph A of the sodium salt offosinopril, recorded in KBr tablet.

FIG. 2 shows the nuclear magnetic resonance spectrum of carbon 13(¹³C-NMR), in solid state, of polymorph A of the sodium salt offosinopril.

FIG. 3 snows the IR spectrum of polymorph B of the sodium salt offosinopril, recorded in KBr tablet.

FIG. 4 shows the nuclear magnetic resonance spectrum of carbon 13(¹³C-NMR), in solid state, of polymorph B of the sodium salt offosinopril.

DESCRIPTION OF THE INVENTION

The authors of the present invention have found that the obtention ofpolymorph A does not necessarily require the crystallization of thesodium salt of fosinopril in a medium containing substantial quantitiesof water, thereby avoiding the problems related to hydrolyticdegradations of the active substance.

The procedure object of the invention is characterized by the formationof a total or partial solution of sodium fosinopril in a solvent ormixture of solvents containing less than 0.2% (v/v) of water withrespect to the total amount of water plus solvent, in a way that:

-   -   (a) the solvent is selected from those containing oxygen in        their molecule and the nitriles or mixtures thereof, provided        that the solvent or mixture of solvents contains more than 0.4%        (v/v) of a C₁-C₄ aliphatic alcohol, linear or ramified, in which        case polymorph A crystallizes at a temperature ranging between        0° C. and 50° C. and separates from the mixture, or    -   (b) the solvent is tetrahydrofuran, with no other solvent        mixture, in this case, when polymorph A is seeked, the starting        point is a partial solution of the sodium salt of fosinopril        crystallized at a temperature between 0° C. and 50° C., or the        starting point is a total solution of this salt crystallized at        a temperature between 20° C. and 35° C., and when polymorph B is        seeked, the starting point is a total solution of the sodium        salt of fosinopril crystallized at a temperature between 0° C.        and 5° C., and the polymorph obtained in each case is separated        from the mixture.

For the purposes of this invention, and unless expressly statedotherwise, a solution of the fosinopril salt in the solvent or solventmixture is to be understood as any degree of solution, with totalsolution of the product not being necessary at the beginning of theprocess.

In the case of option (a) above, the following solvents may be listedamong those containing oxygen in their molecule: the C₁-C₆ aliphaticalcohols, linear or ramified, such as methanol, ethanol, n-propanol,isopropanol, n-butanol, etc.; aliphatic cyclic alcohols, such ascyclohexanol; dioles, such as ethylene glycol, 1,2-propylene glycol,1,3-propanodiole, 1,4-butanodiole, etc.; C₁-C₆ aliphatic ketones, linearor ramified, such as acetone, methylethylketone, methylisobutylketone,etc.; cyclic aliphatic ketones, such as cyclohexanone; low chainaliphatic esters, such as ethyl acetate; low chain aliphatic ethers,such as ethyl ether, isopropylic ether, etc.; cyclic aliphatic ethers,such as tetrahydrofuran and dioxane.

Among the solvents which contain oxygen in their molecule, acetone,methylethylketone and tetrahydrofuran are preferably used; among thenitrile-type solvents, acetonitrile is preferred.

A mandatory condition for option (a) is that the solvent system containsmore than 0.4% (v/v) of a C₁-C₄ aliphatic alcohol, linear or ramified,of which methanol and isopropanol are usually preferred. The proportionof alcohol in the solvent system is preferably between 1% and 5% (v/v).

The previously obtained sodium salt of fosinopril itself may be used asstarting point, whether in the form of polymorph A, polymorph B or amixture of both polymorphs, in which case this salt is mixed with thesolvent system and then stirred at the prescribed temperature for thetime required for the formation of the desired polymorph.

The sodium salt of fosinopril can also be formed in the selected solventsystem itself by adding non-salified fosinopril and the sodium salt ofan aliphatic carboxylic acid, linear or ramified and of chain equal toor higher than C₅, preferably sodium 2-ethylhexanoate and the sodiumsalt of pivalic acid.

In the case of option (a), a crystallization temperature between 35° C.and 45° C. is preferred; however, at the time of substance isolation,e.g. by means of filtration, it is advisable to cool off the mixture ata temperature between 15° C. and 25° C.

A preferred embodiment of the invention comprises mixing a solution ofan aliphatic carboxylic acid, linear or ramified and of chain equal toor higher than C₅, in a solvent selected from those containing oxygen intheir molecule and the nitriles or mixtures thereof, with a sodiummethoxide solution in methanol and with a fosinopril solution in theselected solvent, so that the resulting mixture has a water contentlower than 0.2% and a methanol content higher than 0.4% with respect tothe total volume of the mixture, and proceeding with crystallization ata temperature between 0° C. and 50° C. with further separation from themixture of the precipitated crystals of sodium fosinopril polymorph A.

In the above embodiment the following aspects are preferred,independently or altogether: aliphatic carboxylic acid is selected from2-ethylhexanoic acid and pivalic acid; the aliphatic carboxylic acid andsodium methoxide ratios are close to stoichiometric; the sodium saltratio of the aliphatic carboxylic acid as related to fosinopril isbetween 1.0 and 1.2 versus the stoichiometric ratio; methanol content isbetween 1% and 5% (v/v) of total water plus solvent; the solution of thesodium salt of the aliphatic carboxylic acid is added to the fosinoprilsolution; the crystallization temperature is between 35° C. and 45° C.;and the mixture is cooled off at a temperature between 15° C. and 25° C.before polymorph A crystals of the sodium salt of fosinopril areseparated from the mixture.

Another preferred embodiment of the invention comprises mixing thesodium salt of an aliphatic carboxylic acid, linear or ramified and ofchain equal to or higher than C₅, and a solution of fosinopril in asolvent selected from those containing oxygen in their molecule and thenitrites or mixtures thereof, so that the resulting mixture has a watercontent lower than 0.2% and a linear or ramified C₁-C₄ aliphatic alcoholcontent higher than 0.4% with respect to the total volume of themixture, and crystallizing at a temperature between 0° C. and 50° C.,with further separation from the mixture of the precipitated crystals ofsodium fosinopril polymorph A.

In the above embodiment the following aspects are preferred,independently or altogether: the aliphatic carboxilic acid is selectedfrom 2-ethylhexanoic acid and pivalic acid; the sodium salt ratio ofaliphatic carboxilic acid as related to fosinopril is between 1.0 and1.2 versus the stoichiometric ratio; the linear or ramified C₁-C₄aliphatic alcohol is methanol or isopropanol and its content is between1% and 5% (v/v) of total water plus solvent; the crystallizationtemperature is between 20° C. and 25° C.; and the mixture is cooled offat a temperature between 15° C. and 25° C. before polymorph A crystalsof the sodium salt of fosinopril are separated from the mixture.

Another preferred embodiment of the invention comprises mixing thesodium salt of fosinopril, in either of its crystalline forms or amixture thereof, with a solvent selected from those containing oxygen intheir molecule and the nitrites or mixtures thereof, so that theresulting mixture has a water content lower than 0.2% and a content oflinear or ramified C₁-C₄ aliphatic alcohol higher than 0.4% with respectto the total volume of the mixture, and proceeding with crystallizationat a temperature between 0° C. and 50° C., with further separation fromthe mixture of the precipitated crystals of sodium fosinopril polymorphA.

In the above embodiment the following aspects are preferred,independently or altogether: the linear or ramified C₁-C₄ aliphaticalcohol is methanol or isopropanol and its content is between 1% and 5%(v/v) of total water plus solvent; the crystallization temperature isbetween 35° C. and 45° C.; and the mixture is cooled off at atemperature between 15° C. and 25° C. before polymorph A crystals of thesodium salt of fosinopril are separated from the mixture.

Another preferred embodiment of the invention comprises mixingfosinopril and the sodium salt of an aliphatic carboxylic acid, linearso ramified and of chain equal to or higher than C₅, in tetrahydrofuranso that the resulting mixture has a water content lower than 0.2% withrespect to the total volume of the mixture, and proceeding withcrystallization at a temperature between 20° C. and 35° C., with furtherseparation from the mixture of the precipitated crystals of sodiumfosinopril polymorph A.

Another preferred embodiment of the invention comprises mixingfosinopril and the sodium salt of an aliphatic carboxylic acid, linearor ramified and of chain equal to or higher than C₅, in tetrahydrofuranuntil total solution is formed, so that the resulting solution has awater content lower than 0.2% with respect to the total volume of themixture, and proceeding with crystallization at a temperature between 0°C. and 5° C., with further separation from the mixture of theprecipitated crystals of sodium fosinopril polymorph B.

In the two previous embodiments, the aliphatic carboxylic acid isselected preferably from 2-ethylhexanoic acid and pivalic acid.

Finally, another preferred embodiment of the invention comprises mixingthe sodium salt of fosinopril, in either of its crystalline forms or amixture thereof, in tetrahydrofuran so that the resulting mixture has awater content lower than 0.2% with respect to the total volume of themixture, and proceeding with crystallization at a temperature between20° C. and 35° C., with further separation from the mixture of theprecipitated crystals of sodium fosinopril polymorph A.

The examples that follow are outlined to provide the expert with asufficiently clear and complete explanation of this invention, butshould not be considered as limitations on the essential aspects of theobject of the invention, as exposed in the previous sections of thisdescription.

EXAMPLES Example 1 Obtention of Polymorph A of the Sodium Salt ofFosinopril

7.0 kg of 2-ethylhexanoic acid are added to 25 kg of anhydrous acetone(water content lower than 0.2% v/v, cooled off between 0° C. and 5° C.,and 9.0 kg of a sodium methoxide solution in 30% methanol are addedgradually. The resulting solution is added to a mixture of 22 kg offosinopril and 160 kg of anhydrous acetone heated between 35° C. and 45°C. The mixture is then cooled off at room temperature and the sodiumfosinopril crystals are separated by filtration and vacuum-dried toyield 20.7 kg of polymorph A (90% of theoretical yield). The IR spectrumand the ¹³C-NMR spectrum are shown in FIGS. 1 and 2, respectively. Noneof the spectrums show significant amounts of polymorph B.

Example 2 Obtention of Polymorph B of the Sodium Salt of Fosinopril

2.0 g of sodium 2-ethylhexanoate are added to a solution of 5.5 gfosinopril in 60 mL of tetrahydrofuran (water content according toKarl-Fisher lower than 0.2%) cooled off between 0° C. and 5° C. Afterone-hour stirring at the indicated temperature, the suspension isfiltered, the filtered precipitate is washed with tetrahydrofuran,cooled off between 0° C. and 5° C., and vacuum-dried to yield 5.04 g ofpolymorph B of the sodium salt of fosinopril. The IR spectrum and the¹³C-NMR spectrum are shown in FIGS. 3 and 4, respectively. None of thespectrums show significant amounts of polymorph A.

Example 3 Obtention of Polymorph A of the Sodium Salt of Fosinopril

3.5 g of sodium 2-ethylhexanoate are added to a solution of 12.0 g offosinopril in 330 mL of tetrahydrofuran (water content according toKarl-Fisher lower than 0.2%), kept between 20° C. and 30° C. After30-minute stirring at the indicated temperature, the suspension isfiltered, the filtered precipitate is washed with tetrahydrofuran keptbetween 20° C. and 30° C., and vacuum-dried to yield 9.8 g of polymorphA of the sodium salt of fosinopril.

Example 4 Obtention of Polymorph A of the Sodium Salt of Fosinopril

3.5 g of sodium 3-ethylhexanoate are added at 25° C. to a solution offosinopril (10.0 g) in tetrahydrofuran (130 mL) (water content accordingto Karl-Fisher lower than 0.2%) containing 1.0% of methanol (v/v). Themixture is kept at that temperature and stirred for one hour, thecrystals of sodium fosinopril are filtered and vacuum-dried to yield 9.6g of polymorph A.

Example 5 Obtention of Polymorph A of the Sodium Salt of Fosinopril

Proceeding as in example 4, but replacing tetrahydrofuran withmethylethylketone (130 mL;, 11.4 g of polymorph A of the sodium salt offosinopril are obtained.

Example 6 Obtention of Polymorph A of the Sodium Salt of Fosinopril

Proceeding as in example 4, but replacing tetrahydrofuran withacetonitrile (130 mL), 9.7 g of polymorph A of the sodium salt offosinopril are obtained.

Example 7 Obtention of polymorph A of the Sodium Salt of Fosinopril

Proceeding as in example 4, but replacing tetrahydrofuran with acetone(130 mL) and methanol by isopropanol (1.3 mL), 11.3 g of polymorph A ofthe sodium salt of fosinopril are obtained.

Example 8 Obtention of Polymorph A of the Sodium Salt of Fosinopril

A suspension of 2.8 g of polymorph B of fosinopril is stirred for onehour at room temperature in 29 mL of acetone (water content according toKarl-Fisher lower than 0.2% containing 0.8 mL of methanol (2.7% v/v).The precipitate is filtered, washed with acetone and vacuum-dried toyield 2.3 g of polymorph A of sodium fosinopril.

1. A procedure for the selective preparation of the crystallinepolymorphs of the sodium salt of fosinopril, characterized by theformation of a total or partial solution of sodium fosinopril in asolvent or mixture of solvents containing less than 0.2% (v/v) of waterwith respect to total water plus solvent, wherein: (a) the solvent isselected from those containing oxygen in their molecule and the nitrilesor mixtures thereof, provided that the solvent or mixture of solventscontains more than 0.4% (v/v) of a C₁-C₄ aliphatic alcohol, linear orramified, in which case polymorph A crystallizes at a temperatureranging between 0° C. and 50° C. and separates from the mixture, or (b)the solvent is tetrahydrofuran, with no other solvent mixture, in thiscase, when polymorph A is seeked, the starting point is a partialsolution of the sodium salt of fosinopril crystallized at a temperaturebetween 0° C. and 50° C., or the starting point is a total solution ofthis salt crystallized at a temperature between 20° C. and 35° C., andwhen polymorph B is seeked, the starting point is a total solution ofthe sodium salt of fosinopril crystallized at a temperature between 0°C. and 5° C., and the polymorph obtained in each case is separated fromthe mixture.
 2. The procedure according to claim 1, wherein the solventcontaining oxygen in its molecule is selected from: methanol, ethanoln-propanol, isopropanol, n-butanol, cyclohexanol, ethylene glycol,1,2-propylene glycol, 1,3-propanodiole, 1,4-butanodiole; acetone,methylethylketone, methylisobutylketone; cyclohexanone; ethyl acetate;ethyl ether, isopropylic ether, tetrahydrofuran and dioxane.
 3. Theprocedure according to claim 1 wherein the solvent is selected fromacetone, methylethylketone, tetrahydrofuran and acetonitrile, ormixtures thereof.
 4. The procedure according to claim 1, wherein theC₁-C₄ aliphatic alcohol, linear or ramified, is selected from methanoland isopropanol, and the proportion of said alcohol in the solventsystem is between 1% and 5% (v/v).
 5. The procedure according to claim2, wherein the total or partial solution of sodium fosinopril isprepared by adding non-salified fosinopril to the solvent system and bythe addition or in situ formation of sodium salt of an aliphaticcarboxylic acid, linear or ramified and of chain equal to or higher thanC₅.
 6. The procedure according to claim 5, wherein the aliphaticcarboxylic acid is selected from 2-ethylhexanoic acid and pivalic acid.7. The procedure according to claim 5, wherein it comprises mixing asolution of the aliphatic carboxylic acid in a solvent selected fromthose containing oxygen in their molecule and the nitriles or mixturesthereof, with a sodium methoxide solution in methanol and with afosinopril solution in the selected solvent, so that the resultingmixture has a water content lower than 0.2% and a methanol contenthigher than 0.4% with respect to the total volume of the mixture, andproceeding with crystallization at a temperature between 0° C. and 50°C., with further separation from the mixture of the precipitatedcrystals of sodium fosinopril polymorph A.
 8. The procedure according toclaim 7, wherein, independently or altogether, the followingcharacteristics are comprised: the aliphatic carboxylic acid and sodiummethoxide ratios match stoichiometric ratios, the sodium salt ratio ofthe aliphatic carboxylic acid as related to the fosinopril is between1.0 and 1.2 versus the stoichiometric ratio; the methanol content isbetween 1% and 5% (v/v) of total water plus solvent; the solution of thesodium salt of the aliphatic carboxylic acid is added to the fosinoprilsolution; the crystallization temperature is between 35° C. and 45° C.;and the mixture is cooled off at a temperature between 15° C. and 25° C.before polymorph A crystals of the sodium salt of fosinopril areseparated from the mixture.
 9. The procedure according to claim 5,wherein it comprises mixing the sodium salt of the aliphatic carboxylicacid and a solution of fosinopril in a solvent selected from those whichcontain oxygen in their molecule and the nitriles or mixtures thereof,so that the resulting mixture has a water content lower than 0.2% and alinear or ramified C₁-C₄ aliphatic alcohol content higher than 0.4% withrespect to the total volume of the mixture, and proceeding withcrystallization at a temperature between 0° C. and 50° C., with furtherseparation from the mixture of the precipitated crystals of sodiumfosinopril polymorph A.
 10. The procedure according to claim 9, wherein,independently or altogether, the following characteristics arecomprised: the aliphatic carboxylic acid is selected from2-ethylhexanoic acid and pivalic acid; the sodium salt ratio ofaliphatic carboxylic acid as related to fosinopril is between 1.0 and1.2 versus the stoichiometric ratio; the linear or ramifiedC₁-C₄aliphatic alcohol is methanol or isopropanol and its content isbetween 1% and 5% (v/v) of total water plus solvent; the crystallizationtemperature is between 35° C. and 45° C.; and the mixture is cooled offat a temperature between 15° C. and 25° C. before polymorph A crystalsof the sodium salt of fosinopril are separated from the mixture.
 11. Theprocedure according to claim 1, wherein the total or partial solution ofsodium fosinopril is prepared by adding the sodium salt of fosinopril tothe solvent system, in either of its crystalline forms A or B or amixture of both.
 12. The procedure according to claim 11, wherein itcomprises mixing the sodium salt of fosinopril with a solvent selectedfrom those containing oxygen in their molecule and the nitriles ormixtures thereof, so that the resulting mixture has a water contentlower than 0.2% and a content of a linear or ramified C₁-C₄ aliphaticalcohol higher than 0.4% with respect to the total volume of themixture, and proceeding with crystallization at a temperature between 0°C. and 50° C., with further separation from the mixture of theprecipitated crystals of sodium fosinopril polymorph A.
 13. Theprocedure according to claim 12, wherein independently or altogether,the following characteristics are comprised: the linear or ramifiedC₁-C₄ aliphatic alcohol is methanol or isopropanol and its content isbetween 1% and 5% (v/v) of total water plus solvent; the crystallizationtemperature is between 35° C. and 45° C.; and the mixture is cooled offat a temperature between 15° C. and 25° C. before polymorph A crystalsof the sodium salt of fosinopril are separated from the mixture.
 14. Theprocedure according to claim 5, wherein it comprises mixing fosinopriland the sodium salt of aliphatic carboxylic acid in tetrahydrofuran, sothat the resulting mixture has a water content lower than 0.2% withrespect to the total volume of the mixture, and proceeding withcrystallization at a temperature between 20° C. and 35° C., with furtherseparation from the mixture of the precipitated crystals of sodiumfosinopril polymorph A.
 15. The procedure according to claim 5, whereinit comprises mixing fosinopril and the sodium salt of aliphaticcarboxylic acid in tetrahydrofuran until a total solution is formed, sothat the resulting solution has a water content lower than 0.2% withrespect to the total volume of the mixture, and proceeding withcrystallization at a temperature between 0° C. and 5° C., with furtherseparation from the mixture of the precipitated crystals of sodiumfosinopril polymorph B.
 16. The procedure according to claim 14, whereinthe aliphatic carboxylic acid is selected from 2-ethylhexanoic acid andpivalic acid.
 17. The procedure according to claim 11, wherein itcomprises mixing the sodium salt of fosinopril in tetrahydrofuran, sothat the resulting mixture has a water content lower than 0.2% withrespect to the total volume of the mixture, and proceeding withcrystallization at a temperature between 20° C. and 35° C., with furtherseparation from the mixture of the precipitated crystals of sodiumfosinopril polymorph A.